Communication Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX
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Research Experience for the Organic Chemistry Laboratory: A Student-Centered Optimization of a Microwave-Enhanced Williamson Ether Synthesis and GC Analysis Marsha R. Baar* Department of Chemistry, Muhlenberg College, Allentown, Pennsylvania 18104, United States S Supporting Information *
ABSTRACT: An inquiry-based experiment for the organic chemistry laboratory was developed to provide students with a cognitively rich research experience. Student teams were charged with optimizing the reaction conditions for the Williamson ether synthesis of 2fluorophenetole from 2-fluorophenol, ethyl bromide, and potassium carbonate in either absolute ethanol or acetonitrile. Microwave acceleration of this SN2 reaction followed by rapid GC−MS analysis allowed students to review results, revise experimental conditions, and repeat the modified reaction and its analysis within a 3 h laboratory period. Variables that could be manipulated were reagent equivalencies, solvents and their volume, microwave reaction time, temperature, and wattage. Post-laboratory, all team data were available to the entire class for additional evaluation and each student was required to suggest new conditions for improvement in his/her laboratory report. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Nucleophilic Substitution, Ethers, Collaborative/Cooperative Learning, Hands-On Learning/Manipulatives, Student-Centered Learning, Inquiry-Based/Discovery Learning, Problem Solving/Decision Making
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INTRODUCTION Undergraduates must be exposed to research methodology as it provides an opportunity for key scientific activities such as experimental design, discovery, collaboration, reasoning from data, and modification of conditions for subsequent investigations. There are excellent laboratory experiments published in this Journal that incorporate many of these features.1 However, none include the critical revision of reaction conditions based on data analysis followed by immediate retesting. The inability to rerun the modified experiment is primarily due to time constraints. Recently, a student-centered experimental article appeared in this Journal which cited the supporting educational literature to justify the shift from “expository ‘cook book’ laboratories to discovery based” ones.2 The authors described a butylation of theophylline which required student teams to adapt a literature reaction by reducing the scale, varying reagent equivalencies, and converting a reflux to microwave conditions in an attempt to optimize the alkylation. This experiment achieved all our abovementioned goals. What enabled this more cognitively rich butylation was monomode microwave heating to accelerate the reaction’s rate to within minutes followed by a quick HPLC analysis (∼2−3 min). Students could review the data, propose a new set of variables, and run the reaction under revised conditions along with the associated analysis, all within a 3 h laboratory period. © XXXX American Chemical Society and Division of Chemical Education, Inc.
The organic chemistry laboratory at Muhlenberg College is equipped with monomode microwave ovens and GC−MS rather than HPLC.3 Unfortunately, some of the reactants and products from the butylation of theophylline are not volatile, so this specific alkylation could not be analyzed by GC. However, the appeal of this new pedagogy was the motivation to develop a different SN2 alkylation reaction that involved volatile reagents and product. Thus, the purpose of this article is to share a Williamson ether synthesis that produced 2fluorophenetole from 2-fluorophenol, ethyl bromide, and potassium carbonate in either ethanol or acetonitrile (Scheme 1). Microwave-accelerated reaction of the in situ generated 2fluorophenoxide anion with ethyl bromide formed products within a few minutes that could be separated from starting materials on the GC in a 2.5 min, 150 °C isotherm run. GC− MS conditions and student data are in the Supporting Information; however, a GC is quite sufficient as 2fluorophenol is commercially available and its retention time can be determined beforehand. Ethyl bromide was selected because of its lower toxicity than ethyl iodide and methyl halides. Received: August 4, 2017 Revised: May 26, 2018
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DOI: 10.1021/acs.jchemed.7b00592 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Communication
Scheme 1. Williamson Ether Synthesis of 2-Fluorophenetole from 2-Fluorophenol, Ethyl Bromide, and Potassium Carbonate
plan. Once approved by the instructor, each student ran a second reaction based on the revised conditions, and all data were entered on a Google doc for all students to view and incorporate into their laboratory reports where they were asked to suggest a different set of conditions for a new trial.
Just as critical to a realistic research experience is having a number of variables to manipulate. In addition to changing the molar ratios among 2-fluorophenol, ethyl bromide, and carbonate, the solvents could be varied as well as the microwave oven’s reaction time, reaction temperature, and power. Students were informed that a polar solvent was required to absorb microwave energy, and that ethanol was a better absorber than acetonitrile. However, as taught in lecture, polar aprotic solvents such as acetonitrile are recommended for SN2 reactions. Students could choose to investigate solvent effects by changing solvents and/or reagent concentrations by altering solvent volume. The use of monomode instruments is critical because it provides more consistent results, flexibility in varying parameters, shorter reaction times, and the ability to work on a smaller scale. A multimode microwave oven’s weaker field does not support this new pedagogy due to longer reaction times and batch processing. It is not suggested to run samples with varying characteristics within the same batch, such as different solvents, as they do not absorb microwave energy equally. Also, with the uneven heating within the large cavity oven (hot and cold spots), not utilizing the same positions on the carousel could lead to inconsistent results.4 Bimolecular substitution would have been taught in lecture before this experiment, but the specifics of the Williamson ether synthesis and the role of aprotic polar solvents in facilitating SN2 reactions may or may not have been covered. This SN2 experiment is the student’s first exposure to microwave technology, but they have usually used the GC−MS at least once before. This experiment was performed by 51 chemistry and biochemistry majors over three years. Laboratory sections for our majors hold ∼10 students each and have two monomode microwave ovens and two GC−MS instruments at their disposal.
Results and Conclusions from Student Experience
The first year this experiment was performed it was based on 1.00 mmol of 2-fluorophenol, but the alkylation reaction worked too well. Complete conversion to product occurs within 2 min of heating to 130 °C at 100 W when the equivalencies were 1:1:1. More flexibility in reaction time and temperature was needed, so for subsequent years, the students worked on a 0.50 mmol scale. Most student teams selected 3−4 mL of solvent, so they did not get anywhere near complete conversion at the lower concentration. Complete results for three years of student teams are in the Supporting Information, Tables S2−S7. One team’s results on 0.50 mmol scale are shown in Table 1. The initial plan utilized an extra equivalent of ethyl bromide in Table 1. Reaction Conditions and Results of a Williamson Ether Synthesis Based on 0.50 mmol of 2-Fluorophenola Group and Approach
K2CO3, mmol
EtBr, mmol
Reaction Temp, °C
Reaction Time, Min
Ether, %
Team E First Plan
1
2
75
1.5
22.9
1 1 1
2 2 2
90 105 90
1.5 1.5 2.0
51.7 49.5 66.7
1 2
2 2
90 90
3.0 3.0
68.0 70.4
Team E Second Plan
a
Student Instructions
Team E performed all reactions in 4 mL of ethanol and at 80 W.
4 mL of ethanol with a reaction time of 1.5 min at 80 W. What varied was the reaction temperature. As the temperature increased, a higher percent conversion was noted between 75 and 90 °C, it but leveled at 105 °C. The team decided that heating higher would not be beneficial, so in their next plan, they kept the temperature at 90 °C but increased the reaction time and doubled the amount of carbonate. The longer reaction time was a significant factor, but not the extra equivalent of carbonate. From other results, equivalencies of ethyl bromide, solvent volume, and solvent type were also critical, but not microwave power.
Students were provided with the overall reaction and instructed to calculate a specific millimole amount of all reagents before they arrived in order to facilitate adjusting reagent equivalencies. They were informed that this Williamson ether synthesis produced an 85% yield after stirring in ethanol at room temperature for 24 h. It was suggested that they use the following rule of thumb for determining a reasonable microwave reaction time, namely, that, for every 10 °C increase in temperature, the reaction rate doubles (or reaction time halves). They were also made aware of the following safety guidelines: −130 °C maximum microwave temperature, a solvent volume range 2−6 mL (reaction vessel holds 10 mL), and a power setting range 25−100 W. The week before the experiment, three-student teams were formed and instructed to develop their coherent plan which they e-mailed to the laboratory instructor who suggested alterations if two teams submitted identical plans. Each team member performed the reaction under his/her approved specific conditions. As GC results became available, each team reviewed the data and came up with a second coherent
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EXPERIMENTAL PROCEDURE A detailed procedure and student handout are provided in Supporting Information. Briefly, the student syringed 2fluorophenol (0.50 mmol, 0.045 mL) directly into a 10 mL microwave vessel. In either order, K2CO3 (grams in a plastic weigh boat) and ethyl bromide (mL taken up in a syringe) were measured out and added to the reaction vessel. The solvent and flea stir bar were added, and the reaction vessel was capped and placed on the autosampler’s rack. The instructor assisted B
DOI: 10.1021/acs.jchemed.7b00592 J. Chem. Educ. XXXX, XXX, XXX−XXX
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students to program their microwave method on the computer, and the sample was run. When the vessel was retrieved from the oven, it was cooled in a tap water bath and the contents were filtered through a Hirsch funnel. A portion of the filtrate was pipetted into a 1.5 mL GC vial for analysis.
ORCID
HAZARDS Ethyl bromide, ethyl iodide, ethanol, acetonitrile, and 2fluorophenol are flammable liquids and must be handled in the absence of any ignition source. Dichloromethane is a possible carcinogen. Potassium carbonate and all the chemicals, including the ether product, are irritants, and the phenol can cause burns. Safety goggles and gloves should be worn, and working in a hood is recommended.
ACKNOWLEDGMENTS The author wishes to thank Muhlenberg College’s Provost Office for funding her attendance at the Biennial Conference on Chemical Education (BCCE 2014) where she was able to perform the butylation of theophylline in a workshop led by Shaun Murphree. She would also like to thank her students for their participation.
EVALUATION The assessment of this experiment was both anecdotal and formal. The instructors noted healthy discussions within and between the teams, so student engagement was high. More quantitatively, an examination of the students’ initial and revised plans, for the most part, showed intelligence, excellent reasoning from data that often led to yield improvement, but always useful information. Students were asked questions concerning their understanding of the optimization experiment’s goals on their next week’s lab quiz. In their laboratory report, students explained the reasoning behind their team’s initial coherent and revised plans and their success or lack thereof. Also, each student had to analyze the data from the entire class and what it suggested to him/her for a new trial which he/she had to propose. The report guidelines and one student’s report are included in the Supporting Information. Some students focused on a few variables when evaluating the entire class’ results, while others considered all variables and their interplay. It will be interesting to see if student reasoning improves as more research-style experiments are included in the laboratory curriculum.
(1) Some examples of notable experiments are: (a) Flynn, A. B.; Biggs, R. The Development and Implementation of a Problem-Based Learning Format in a Fourth-Year Undergraduate Synthetic Organic and Medicinal Chemistry Laboratory Course. J. Chem. Educ. 2012, 89 (4), 52−57. (b) Collison, C. G.; Cody, J.; Stanford, C. An SN1-SN2 Lesson in an Organic Chemistry Lab Using Studio-Based Approach. J. Chem. Educ. 2012, 89 (6), 750−754. (c) MacKay, J. A.; Wetzel, N. R. Exploring the Wittig Reaction: A Collaborative Guided-Inquiry Experiment for the Organic Chemistry Laboratory. J. Chem. Educ. 2014, 91 (5), 722−725. (d) Weaver, M. G.; Samoshin, A. V.; Lewis, R. B.; Gainer, M. J. Developing Students’ Critical Thinking, Problem Solving, and Analysis Skills in an Inquiry-Based Synthetic Organic Laboratory Course. J. Chem. Educ. 2016, 93 (5), 847−851. (2) Russell, C. B.; Mason, J. D.; Bean, T. G.; Murphree, S. S. A Student-Centered First-Semester Introductory Organic Laboratory Curriculum Facilitated by Microwave-Assisted Synthesis (MAOS). J. Chem. Educ. 2014, 91 (4), 511−517. (3) Our monomode microwave oven is a CEM Discover outfitted with Explorer autosampler. Our GC−MS is a Shimadzu QP2010SE. (4) Baar, M. R.; Gammerdinger, W.; Leap, J.; Morales, E.; Shikora, J.; Weber, M. H. Pedagogical Comparison of Five Reactions Performed Under Microwave Heating in Multi-mode versus Mono-mode Ovens: Diels-Alder Cycloaddition, Wittig Salt Formation, E2 Dehydrohalogenation to form an Alkyne, Williamson Ether Synthesis, and Fischer Esterification. J. Chem. Educ. 2014, 91 (10), 1720−1724.
Marsha R. Baar: 0000-0001-8464-7757 Notes
The author declares no competing financial interest.
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CONCLUSION Rate acceleration by microwave heating and rapid analysis by GC can facilitate a research experience for students in the introductory organic chemistry laboratory. The described Williamson ether synthesis allowed for greater student participation in experimental design, team work, scientific discovery, and reasoning from data. Critical to this experience was sufficient instrumentation. One monomode microwave oven and one GC instrument for every five students is an appropriate ratio in order to complete two runs within a 3 h lab period.
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REFERENCES
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00592. Student handout, instructor’s notes, tabulated student results, representative GC−MS printouts and GC conditions, report guidelines, and representative student report (PDF, DOCX)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. C
DOI: 10.1021/acs.jchemed.7b00592 J. Chem. Educ. XXXX, XXX, XXX−XXX
